Role of CCR1 in Cytokine Storm & Immunopathology after influenza infection

点击翻译按钮获取中文摘要

Mortality after infection with highly pathogenic influenza viruses, including avian H5N1 virus and the 1918 H1N1 virus, is associated with the propensity of these viruses to induce severe cytokine-mediated immunepathology, characterized by hypoxemia and hemorrhagic inflammatory edema in the lung. In addition, acute pro-inflammatory cytokine production has been correlated with the onset of fatal influenza-associated encephalopathy in children infected with influenza A viruses. Antiviral neuraminidase inhibitors are able to control viral infection if given early to patients, but no drugs have been reported to be effective in treating the cytokine-mediated lung damage. Importantly, the exact source of pathogenic cytokines during influenza infection has been not identified. However, accumulation of monocyte-derived cells in the lungs is associated with the development of lung damage in several inflammatory pulmonary diseases, and these cells have been suggested the major source of inflammatory cytokines after influenza infection. Mechanisms orchestrating the recruitment, differentiation and activation of inflammatory myeloid cells to the lung following flu infection remain elusive. The chemokine receptor CCR1 is expressed by hematopoietic cells, including monocytes, macrophages and DCs, and by some non-bone marrow-derived cells. Our preliminary data demonstrate that CCR1 deletion protects from lethal influenza infection associated immunopathology and mortality. Based on our preliminary results, we hypothesize that CCR1 deficiency prevents influenza-associated mortality by preventing activation of monocyte-derived inflammatory cells within the infected lungs. In this proposal, we will determine how CCR1 deficiency promotes protection from the immunopathology associated with pathogenic influenza infections (Aim 1) and will evaluate the potential therapeutic uses of CCR1 antagonists in treating influenza-associated immunopathology (Aim 2).